Estrogen plays an important role in protecting the health of women. It has been implicated as a significant factor in protecting and maintaining cardiovascular health, bone mass, and mental cognition. The health protective effects of estrogen for women have been proposed as one of the reasons that women in the United States live an average of 71/2 years longer than men. Women form 59% of the U.S. population over age 65 and 72% of the population over age 85.
A woman's endogenous level of estrogen is significantly reduced upon entering menopause or upon premature surgical menopause induced by removal of the uterus and/or ovaries. The amount of a woman's endogenous estrogen is typically reduced to less than 10% of premenopausal levels following natural or surgical menopause. This reduction of endogenous estrogen levels results in the loss of estrogen's health protective effects, particularly with respect to cardiovascular health, bone health, and mental cognition.
Cardiovascular disease is the leading cause of death in women. Compared to men, premenopausal women are relatively protected from cardiovascular disease by estrogen, but gradually lose this protection following menopause as estrogen levels decline. Patterns in Coronary Heart Disease--Morbidity and Mortality in the Sexes: A 26-Year Follow-Up of the Framingham Population, Lerner & Kannel, Amer. Heart J., 111: 383-90 (1986). The onset of cardiovascular disease is hastened in women by prematurely induced surgical menopause and its attendent reduction in endogenous estrogen levels. Time Interval from Castration in Premenopausal Women to Development of Excessive Coronary Atherosclerosis, Parrish, H. M. et al., Amer. J. Obst. Gynecol., 99: 155-62 (1967).
Osteoporosis, while not a leading cause of mortality in post-menopausal women, is a substantial contributor to morbidity in such women. Osteoporosis is present in approximately one in four women over the age of 65, and typically develops after post-menopausal reduction of endogenous estrogen. Loss of bone mineral density, the key indicator of osteoporosis, is also hastened by prematurely induced surgical menopause and its attendent reduction in endogenous estrogen levels. Relative Contributions of Aging and Estrogen Deficiency to Postmenopausal Bone Loss, Richeson, L. S. et al., N. Eng. J. Med., 311: 1273-75 (1984).
Loss of cognitive function is also significantly more likely to occur in postmenopausal women as a result of the loss of the protective effects of estrogen. Loss of cognitive function is associated with decreased choline acetyltransferase ("ChAT") and the loss of cholinergic neurons. Estrogen has been identified as an agent which upregulates ChAT production, thereby inhibiting the loss of cognitive function associated with decreased ChAT. Ovarian Steroid Deprivation Results in a Reversible Learning Impairment and Compromised Cholinergic Function in Female Sprague-Dawley Rats, Singh et al., Brain Research, 644: 305-12 (1994).
The reduction of endogenous estrogen as a result of natural or surgical menopause also has other deleterious health effects. Reduced estrogen levels have been implicated in the development of urinary incontinence as a result of the effect of the loss of estrogen on the smooth muscle cells of the urethra. Reduced estrogen levels are also implicated in significant weight and fat mass gain in postmenopausal women. Impact of Hormone Replacement Therapy on the Body Mass and Fat Compositions of Menopausal Women: A Cross-Sectional Study, Sayegh, R. et al., Menopause, Vol. 6, No. 4, 312-15 (1999).
Hormone replacement therapy is currently utilized as a treatment to increase the level of estrogen in women having reduced levels of endogenous estrogen resulting from natural or surgical menopause. Supplemental estrogen is provided to the women in order to inhibit, ameliorate, or prevent diseases or conditions which result from the reduction of endogenous estrogen.
The estrogen provided in hormone replacement therapy is particularly useful to ameliorate the diseases and conditions noted above-cardiovascular disease and coronary heart disease, osteoporosis, declining mental cognition, urinary incontinence, and weight and fat mass gain in postmenopausal women, as well as inhibiting vasomotor symptoms resulting from a reduction in endogenous estrogen such as hot flush. Administration of unopposed conjugated estrogen has been found to reduce the relative risk of coronary disease in postmenopausal women to a level of 0.41 to 0.56 that of untreated postmenopausal women. Estrogen Replacement Therapy and Coronary Disease: A Quantitative Assessment of the Epidemiological Evidence, Stampfer & Colditz, Prev. Med, 20: 47-63 (1991). Unopposed estrogen has been shown to prevent menopausal bone loss at a number of skeletal sites, and tends to maintain bone mass at the level present when administration is initiated. Long Term Prevention of Post-Menopausal Osteoporosis by Estrogen, R. Lindsay et al., Lancet, 1: 1038-41 (1976); HRT and Osteoporosis, J. Compston, Brit. Med Bull., 48: 304-44 (1992). As a result, estrogen is regarded as a first-line therapy for postmenopausal women having reduced bone mineral density. Treatment of postmenopausal women with unopposed estrogen has also been shown to have beneficial effects on cognitive function by maintaining short term memory and ameliorating clinical symptoms of Alzheimer's disease. The Influence of Estrogens On the Psyche In Climacteric and Post-Menopausal Women, Furuhjelm & Fedor-Freybergh, Consesus on Menopause Research, Van Keep, Greenblatt, & Albeaux-Fernet (eds.), University Park Press, Baltimore, 84-93 (1976); Estrogen and/or Androgen Replacement Therapy and Cognitive Functioning in Surgically Menopausal Women, B. Sherwin, Psychoneuroendocrinology, 13: 345-47 (1988); Estrogen and Memory in Postmenopausal Women; B. Sherwin, Third Annual Meeting, North American Menopause Society, 50 (1992); Senile Dementia-Alzheimer's Type and Estrogen, Honjo et al., Hormone Metab. Res., 27: 204-07 (1995). Hormone replacement therapy is also indicated to treat vasomotor symptoms such as hot flush, which are associated with a decrease in endogenous estrogen levels in women. Determining the Role of Long-Term Hormone Therapy After Menopause in the Context of Primary Preventive Health Care for Women, Wolf H. Utian, Menopause, Vol. 3, No.2, 65-70 (1996).
Unfortunately, administration of unopposed estrogen to postmenopausal women presents serious health risks. Estrogen has a stimulatory effect on the growth of uterine and breast tissues, and treatment of postmenopausal women with estrogen is associated with significant increases in uterine and breast cancer. Unopposed estrogen users are 3-6 times more likely than non-users to develop endometrial cancer after 3-10 years of use, and are 10 times more likely to develop endometrial cancer after 10 years of use. Hormone Replacement and Cancer, E. Barrett-Conner, Brit. Med. Bull., 48:345-55 (1992). Administration of estrogen over a long period of time, e.g. 10-15 years, is associated with a 30-50% increase in the risk of breast cancer, although short term administration of estrogen, e.g. less than 5 years, appears to have no adverse effects. Selective Estrogen Receptor Modulators, Kauffman & Bryant, DN&P, 8(9): 531-539 (November 1995).
Currently prescribed hormone replacement therapies utilize a progestin which is co-administered with estrogen to limit the estrogen's uterine stimulatory effects, thereby reducing the risk of endometrial cancer. Addition of progestin, however, does not reduce the increased risk of breast cancer induced by administration of estrogen. The Use of Estrogens and Progestins and the Risk of Breast Cancer in Postmenopausal Women, G. Colditz et al., N. Eng. J. Med., 332: 1589-93 (1995). Furthermore, co-administration of progestin has several undesirable side-effects such as continuing menstrual periods, cyclic depression, edema, lower abdominal cramps, breast tenderness, and symptoms like premenstrual syndrome. The disincentives of progestin induced side-effects and the fear of breast cancer combine to 1) substantially reduce the number of postmenopausal women choosing to start a hormone replacement therapy treatment, and 2) once a hormone replacement therapy is started, result in poor compliance with the hormone replacement therapy over an extended period of time, and ultimately, a discontinuance of the therapy.
U.S. Pat. No. 5,516,528 to Hughes et al. provides a novel hormone replacement therapy in which soy derived phytoestrogens are utilized in combination with estrogen, instead of progestin. The soy derived phytoestrogens are selective estrogen receptor modulators which have both estrogenic and anti-estrogenic activity, and act as estrogen antagonists in both uterine and breast tissues. The phytoestrogens, therefore, serve to decrease the risk of both estrogen induced uterine and breast cancers in the hormone replacement therapy. The phytoestrogens have estrogenic activity outside of breast and uterine tissues, and supplement estrogen's cardioprotective effects and bone mineral maintenance effects. The phytoestrogens do not produce the undesirable side effects of progestin such as continuing menstrual periods, breast tenderness, abdominal cramping, or cyclic depression. Therefore, the phtyoestrogen/estrogen hormone replacement therapy offers the benefits of estrogen while reducing the risk of estrogen induced breast and uterine cancer without undesirable side effects which reduce compliance with a hormone replacement therapy utilizing a progestin.
As promising as the phytoestrogen/estrogen hormonal replacement therapy disclosed in the '528 patent appears, it suffers a significant defect. Specifically, the phytoestrogens utilized in the hormone replacement therapy include isoflavones such as daidzein, formononetin, and their glycosides and glycoside conjugates which are metabolized by humans to equol. While less estrogenic than estrogen, equol is substantially more estrogenic than its isoflavone phytoestrogen precursors, and may induce estrogenic-like tissue growth in the breast and uterus. Therefore, inclusion of phytoestrogens which can be metabolized to equol in a phytoestrogen/estrogen hormone replacement therapy is at best counterproductive to the phtyoestrogenic inhibition of estrogen induced breast and endometrial cancer, and at worst actually enhances tissue proliferative estrogenic effects in breast and uterine tissues.
Equol may present a particular problem at the levels of phytoestrogen administration required in the hormone replacement therapy disclosed in the '528 patent. Human consumption of 40 grams of soy per day (containing approximately 120 mg of phytoestrogens) has been shown to increase the urinary levels of equol as much as 1000 fold higher than baseline values. Urinary excretion of equol under these conditions has been shown to exceed 3.5 mg/day, which dwarfs the levels of the principal urinary estrogen excreted in urine in premenopausal women, estrone-glucuronide, typically excreted in amounts from 2 to 27 .mu.g/day. Nonsteroidal Estrogens of Dietary Origin: Possible Roles in Hormone-Dependent Disease, K. Setchell et al., Am. J Clin. Nut., 40: 569-78 (September 1984). The amount of equol which would be produced in response to the hormone replacement therapy of the '528 patent would only enhance the counterproductive effects of equol's relatively potent estrogencity in the therapy.